Circulating Plasma Exosomes in Obstructive Sleep Apnea and Reverse-Dipping Blood Pressure

  1. Abdelnaby Khalyfa1,
  2. David Gozal1,
  3. Wen-Ching Chan2,
  4. Jorge Andrade2 and
  5. Bharati Prasad3⇑
  1. 1Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO, USA
  2. 2Center for Research Informatics, The University of Chicago, Chicago, Illinois, USA
  3. 3Department of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois, USA
  1. Dr Bharati Prasad, MD, MS, Associate Professor of Medicine, Department of Medicine, Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois Hospital and Health Sciences System, 840 S Wood St, MC 719; 9th Floor. E-mail: bpradsad{at}uic.edu

Abstract

Background Obstructive Sleep Apnea (OSA) increases the risk of abnormal non-dipping 24-hour blood pressure profile, an independent risk factor for cardiovascular disease (CVD). We examined differential exosomal miRNA expression in untreated OSA patients with normal dipping blood pressure (NDBP) and reverse dipping blood pressure (RDBP; an extreme form of non-dipping) to understand the mechanisms underlying non-dipping blood pressure in OSA.

Methods 46 patients (RDBP, n=15 versus NDBP, n=31) matched for OSA severity (respiratory event index, 32.6±22.5 h−1 versus 32.2±18.1 h−1, p=0.9), age (54.8±12.9 versus 49±9.9 years, p=0.09) and body mass index (36.2±6.6 kg·m−2 versus 34.4±6.8 kg·m−2, p=0.4) were included. Plasma exosomes were characterised by flow cytometry, and functional in vitro reporter assays were conducted on cultured endothelial cells. Exosome miRNA cargo was profiled with microarrays followed by bioinformatics analyses.

Results Exosomes from RDBP patients increased the permeability of endothelial cell tight-junctions and adhesion molecule expression. Principal component analyses of miRNA array data showed strict separation and identification of the two groups. A restricted and validated signature of exosomal miRNAs were identified in RDBP versus NDBP group. Their predicted target genes involved PI3K-Akt (p=0.004), Ras (p=3.42E-05), Wnt (p=0.003), and HIF-1 signalling (p=0.04), inflammatory mediator regulation of TRP channels (p=0.01), and several cancer-related pathways.

Conclusions Patients with RDBP have altered miRNA cargo in circulating exosomes that invoke in vitro endothelial dysfunction. A selected number of circulating exosomal miRNAs play an important role in abnormal circadian regulation of blood pressure and may provide prognostic biomarkers of CVD risk in OSA.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Khalyfa has nothing to disclose.

Conflict of interest: Dr. Gozal has nothing to disclose.

Conflict of interest: Dr. Chan has nothing to disclose.

Conflict of interest: Dr. Andrade has nothing to disclose.

Conflict of interest: Dr. Prasad has nothing to disclose.

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  • Received May 30, 2019.
  • Accepted October 12, 2019.